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WO2019139365A1 - Nouveau dérivé d'oxazole phénylsulfonyle et son utilisation - Google Patents

Nouveau dérivé d'oxazole phénylsulfonyle et son utilisation Download PDF

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Publication number
WO2019139365A1
WO2019139365A1 PCT/KR2019/000373 KR2019000373W WO2019139365A1 WO 2019139365 A1 WO2019139365 A1 WO 2019139365A1 KR 2019000373 W KR2019000373 W KR 2019000373W WO 2019139365 A1 WO2019139365 A1 WO 2019139365A1
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Prior art keywords
substituted
unsubstituted
formula
compound
disease
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Ceased
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PCT/KR2019/000373
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English (en)
Korean (ko)
Inventor
배재성
진희경
이명식
임혜진
안진희
하우샤브하우 쉬배지 파기레
이민재
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Gwangju Institute of Science and Technology
Industry Academic Cooperation Foundation of Yonsei University
SNU R&DB Foundation
Industry Academic Cooperation Foundation of KNU
Original Assignee
Gwangju Institute of Science and Technology
Industry Academic Cooperation Foundation of Yonsei University
Seoul National University R&DB Foundation
Industry Academic Cooperation Foundation of KNU
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Application filed by Gwangju Institute of Science and Technology, Industry Academic Cooperation Foundation of Yonsei University, Seoul National University R&DB Foundation, Industry Academic Cooperation Foundation of KNU filed Critical Gwangju Institute of Science and Technology
Priority to US16/961,348 priority Critical patent/US11345671B2/en
Priority to CN201980016200.7A priority patent/CN111868043B/zh
Publication of WO2019139365A1 publication Critical patent/WO2019139365A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/46—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/42—One oxygen atom attached in position 5

Definitions

  • the present invention relates to novel phenylsulfonyloxazole derivatives and their use, and specifically relates to a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof and a prophylactic, therapeutic or ameliorative treatment for the degenerative neurological disease Lt; / RTI >
  • Neurodegenerative diseases Patients with neurodegenerative disease have abnormalities in their ability to regulate exercise, cognitive function, sensory function, sensory function and autonomic function due to loss or loss of function of nerve cells. During the onset of these degenerative neurological disorders, abnormal substances are deposited in the nerve cells and this often causes neurotoxicity. Therefore, elimination of these neurotoxic agents is considered to be an approach to the prevention and treatment of neurodegenerative diseases.
  • the inventors of the present invention have made the compounds represented by the formula (I) and confirmed that these compounds actually exhibit significant therapeutic effects by controlling abnormal autophagy in the degenerative neurological disease in vivo, thereby completing the present invention.
  • an object of the present invention is to provide a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof:
  • R is hydrogen, hydroxy, cyano (CN), amino, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy ≪ / RTI >
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating degenerative neurological diseases comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition for preventing or treating degenerative neurological diseases comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition for preventing or treating degenerative neurological diseases, which is essentially composed of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • Still another object of the present invention is to provide a food composition for preventing or ameliorating a neurodegenerative disease, which comprises the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a food composition for preventing or ameliorating a neurodegenerative disease comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a food composition for preventing or ameliorating a neurodegenerative disease, which is essentially composed of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • Still another object of the present invention is to provide a process for producing a compound represented by the above formula (1).
  • Another object of the present invention is to provide a use of the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof for the preparation of a preparation for the prophylaxis or treatment of degenerative neurological diseases.
  • the present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
  • R is hydrogen, hydroxy, cyano (CN), amino, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy ≪ / RTI >
  • the present invention provides a pharmaceutical composition for preventing or treating degenerative neurological diseases comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition for preventing or treating degenerative neurological diseases comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition for preventing or treating a neurodegenerative disease which is essentially composed of a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a food composition for preventing or ameliorating a neurodegenerative disease, comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a food composition for preventing or ameliorating a neurodegenerative disease comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a food composition for preventing or improving a neurodegenerative disease which is essentially composed of the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a process for preparing the compound of formula (1), comprising the steps of:
  • step (b) reacting the compound of formula (4) prepared in step (a) with a compound of formula (5) to prepare a compound of formula (6);
  • step (c) reacting the compound of formula (6) prepared in step (b) with the compound of formula (7) to prepare and obtain the compound of formula (1).
  • R is selected from the group consisting of hydrogen, hydroxy, cyano (CN), amino, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Lt; / RTI > alkoxy.
  • the present invention provides the use of a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof for the preparation of a preparation for the prevention or treatment of neurodegenerative diseases.
  • the present invention is characterized by administering to a subject in need thereof an effective amount of a composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient And a method for treating neurodegenerative diseases.
  • R is hydrogen, hydroxy, cyano (CN), amino, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy ≪ / RTI >
  • 'halogen' means fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • &quot means a group -CN.
  • the term " amino " refers to a primary, secondary, or tertiary amino group bonded through a nitrogen atom, wherein the secondary amino group has an alkyl substituent and the tertiary amino group has two similar or different hereinafter defined as having an alkyl substituent), for example, -NH 2, methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidin gavel the like, preferably a primary Amino, C1-C10 alkylamino.
  • &quot nitro " as used herein refers to the group -NO2.
  • substituted includes at least one substituent, for example, a halogen atom, nitro, hydroxy, cyano, amino, thiol, carboxyl, amide, nitrile, sulfide, disulfide, Phenyl, formyl, formyloxy, or formylamino. Unless otherwise specified, or when the structure obtained by such substitution does not significantly adversely affect the properties of the compound represented by formula (1) of the present invention, any of the compounds described for the compound represented by formula Group or structure may be substituted.
  • alkyl used in the present invention includes, unless otherwise indicated, a straight or branched chain having 1 to 10 carbon atoms (C1-C10), more preferably 1 to 6 carbon atoms (C1-C6) (C1-C4) < / RTI > For example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert- butyl, cyclobutyl, cyclopropylmethyl, n-pentyl, isopentyl, neopentyl, Cyclopentyl, cyclobutylmethyl, n-hexyl, isohexyl, cyclohexyl, cyclopentylmethyl and the like.
  • the alkyl may be substituted or unsubstituted alkyl.
  • the substituted alkyl may be, but is not limited to, trifluor
  • alkenyl or alkynyl used in the present invention means a straight or branched chain containing 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, each containing one or more double bonds or triple bonds, Quot; means a hydrocarbon radical having 2 to 4 carbon atoms.
  • the alkenyl or alkynyl may each be substituted or unsubstituted alkenyl or alkynyl.
  • alkoxy used in the present invention means an -O-alkyl group, and the alkyl is as described above. For example, methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy and n-pentoxy.
  • the alkoxy may be substituted or unsubstituted alkoxy.
  • the compound of formula (I) of the present invention may be that wherein R is trifluoromethyl (-CF3), and its more specific form has a structure represented by the following formula 1-1, Methoxy-4- (phenylsulfonyl) -2- (4- (trifluoromethyl) phenyl) oxazole.
  • the pharmaceutically acceptable salt means a salt or complex of formula (I) having a desired biological activity.
  • examples of such salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.
  • carboxylic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid Ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene sulfonic acid, Naphthalene disulfonic acid, and salts formed with organic acids such as poly-galacturonic acid.
  • carboxylic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid Ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene sulfonic acid, Naphthalene disulfonic acid, and salts formed with organic acids such as poly-galacturonic acid.
  • the compounds may also be administered in pharmaceutically acceptable quaternary salts known to those skilled in the art, especially those which are selected from the group consisting of chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, (For example, benzoates, succinates, acetates, glycolates, maleates, malates, fumarates, citrates, tartrates, ascorbates, cinnamoates, mandelate And diphenylacetate).
  • the compounds of formula (I) of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates which can be prepared by conventional methods.
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and diastereoisomers are included within the scope of the present invention.
  • the compound of the present invention When the compound of the present invention is applied to a neurodegenerative disease such as Alzheimer's disease, it has remarkable therapeutic effects such as reduction of A? Plaque, improvement of memory and anxiety, and relief of nerve inflammation by controlling abnormal autophagy. Therefore, the compounds of the present invention can be very usefully used for the development of a preventive or therapeutic agent for degenerative neurological diseases through the control of autophagy. This is well illustrated in the specification of the present invention.
  • the present invention provides a pharmaceutical composition for preventing or treating degenerative neurological diseases, which comprises the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition for preventing or treating degenerative neurological diseases comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition for preventing or treating a neurodegenerative disease, which is essentially composed of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a food composition for preventing or ameliorating a neurodegenerative disease, which comprises the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a food composition for preventing or ameliorating a neurodegenerative disease comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a food composition for preventing or ameliorating a neurodegenerative disease, which is essentially composed of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the degenerative neurological diseases are selected from the group consisting of Alzheimer's disease, Parkinson's disease, dementia, progressive supranuclear palsy, multiple system atrophy, olfactory nuclear-pongo-cerebellar atrophy (OPCA), Shire-Drager syndrome, , Amyotrophic lateral sclerosis (ALS), essential hypertrophy, corticobasal degeneration, diffuse rheumatic disease, parkins-ALS-dementia complex, Pick's disease, cerebral ischemia and cerebral infarction , But is not limited thereto.
  • the pharmaceutical composition according to the present invention may be formulated into a suitable form together with a compound of the above-mentioned formula (I) or a pharmaceutically acceptable salt thereof alone or together with a pharmaceutically acceptable carrier, and may further contain an excipient or diluent can do.
  • &Quot; Pharmaceutically acceptable " as used herein refers to a nontoxic composition that is physiologically acceptable and does not normally cause an allergic reaction such as gastrointestinal disorder, dizziness, or the like when administered to humans.
  • the pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration.
  • Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. In addition, it may contain various drug delivery materials used for oral administration to peptide preparations.
  • the carrier for parenteral administration may contain water, a suitable oil, a saline solution, an aqueous glucose and a glycol, and may further contain a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid.
  • Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.
  • the pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, etc. in addition to the above components.
  • composition of the present invention can be administered to mammals including humans by any method.
  • it can be administered orally or parenterally.
  • Parenteral administration methods include, but are not limited to, intravenous, intraperitoneal, intracerebral, subcutaneous, intramuscular, intravenous, intraarterial, intrathecal, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, But are not limited to, injection or infusion by intranasal, intestinal, topical, sublingual, rectal, or intralesional routes, or injection or infusion by a sustained release system as described below.
  • the compound of Formula 1 may be administered systemically or locally.
  • composition of the present invention can be formulated into oral preparations or parenteral administration preparations according to the administration route as described above.
  • the composition of the present invention may be formulated into a powder, a granule, a tablet, a pill, a sugar, a tablet, a liquid, a gel, a syrup, a slurry, .
  • an oral preparation can be obtained by combining the active ingredient with a solid excipient, then milling it, adding suitable auxiliaries, and then processing the mixture into a granular mixture.
  • excipients include, but are not limited to, sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, and starches including corn starch, wheat starch, rice starch and potato starch, Cellulose such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose and the like, fillers such as gelatin, polyvinylpyrrolidone and the like.
  • crosslinked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may optionally be added as a disintegrant.
  • the pharmaceutical composition of the present invention may further comprise an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent.
  • a preparation for parenteral administration it can be formulated by a method known in the art in the form of injection, cream, lotion, external ointment, oil, moisturizer, gel, aerosol and nasal aspirate.
  • formulations may include all commonly known formulations in all pharmaceutical chemistries.
  • the total effective amount of the composition of the present invention may be administered to a patient in a single dose and may be administered by a fractionated treatment protocol administered over a prolonged period of time in multiple doses.
  • the content of the active ingredient may be varied depending on the degree of the disease.
  • the preferred total dosage of the pharmaceutical compositions of the present invention may be from about 1 ng to 10 mg, most preferably from 1 ug to 1 mg, if the body weight of the patient per day is typically 60 kg.
  • the dosage of the pharmaceutical composition may be determined depending on various factors such as the formulation method, administration route and frequency of treatment, as well as the patient's age, body weight, health condition, sex, severity of disease, diet and excretion rate, It will be possible to determine the appropriate effective dose of the composition of the present invention by those of ordinary skill in the art in view of this point.
  • the pharmaceutical composition according to the present invention is not particularly limited to its formulation, administration route and administration method as long as the effect of the present invention is exhibited.
  • the compound according to the present invention can be formulated into various forms depending on the purpose. Examples of formulations for the composition of the present invention are illustrated below.
  • tablets were prepared by tableting according to a conventional method for producing tablets.
  • the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.
  • composition for food according to the present invention includes all forms such as functional food, nutritional supplement, health food and food additives. These types can be prepared in various forms according to conventional methods known in the art.
  • the food composition itself of the present invention may be prepared in the form of tea, juice, and drink and then consumed, granulated, encapsulated, and powdered.
  • the food composition of the present invention may be prepared in the form of a composition by mixing with known substances or active ingredients known to be effective for preventing, improving or treating neurodegenerative diseases.
  • Functional foods also include beverages (including alcoholic beverages), fruits and their processed foods (such as canned fruits, bottled, jam, maalmalade, etc.), fish, meats and processed foods such as ham, (Such as udon, buckwheat noodles, ramen noodles, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, , Vegetable protein, retort food, frozen food, various kinds of seasoning (for example, soybean paste, soy sauce, sauce, etc.).
  • beverages including alcoholic beverages
  • fruits and their processed foods such as canned fruits, bottled, jam, maalmalade, etc.
  • fish meats and processed foods
  • meats and processed foods such as ham, (Such as udon, buckwheat noodles, ramen noodles, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, , Vegetable protein, retort food, frozen food, various kinds of seasoning (for example, soybean paste, soy sauce, sauce, etc.).
  • the health beverage composition may contain various flavors or natural carbohydrates as an additional ingredient such as a conventional beverage.
  • natural carbohydrates are monosaccharides such as glucose and fructose, polysaccharides such as disaccharides such as maltose and sucrose, dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol.
  • sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like.
  • the ratio of the natural carbohydrate may be generally about 0.01 to 0.20 g, preferably about 0.04 to 0.10 g per 100 g of the composition of the present invention.
  • composition of the present invention may further contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acids and salts thereof, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, A carbonating agent used in a carbonated beverage, and the like.
  • composition of the present invention may contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. Although the ratio of such additives is not critical, it is generally selected in the range of 0.01 to 0.20 parts by weight per 100 parts by weight of the composition of the present invention.
  • the preferred content of the compounds in the food composition according to the present invention is not particularly limited, but is preferably 0.01 to 50% by weight based on the total weight of the final product.
  • it may be used in the form of powder or concentrate.
  • the present invention also provides a process for preparing a compound of formula 1, comprising the steps of:
  • step (b) reacting the compound of formula (4) prepared in step (a) with a compound of formula (5) to prepare a compound of formula (6);
  • step (c) reacting the compound of formula (6) prepared in step (b) with the compound of formula (7) to prepare and obtain the compound of formula (1).
  • R is selected from the group consisting of hydrogen, hydroxy, cyano (CN), amino, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, Lt; / RTI > alkoxy.
  • the solvent used in the above steps (a) to (c) of the present invention is not particularly limited as long as it dissolves the starting material and does not inhibit the reaction.
  • the solvent include tetrahydrofuran, 1,2-dimethoxyethane, Ether solvents such as ethyl ether or dioxane; Aromatic hydrocarbon solvents such as benzene, toluene or xylene; Aliphatic hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, trichloroethane, tetrachloroethane, dichloroethylene, trichlorethylene and tetrachlorethylene; Amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone; Nitrile solvents such as acetonitrile, propionitrile, butyronitrile and valeronitrile; An organic solvent such as dimethylsulfoxide; Alcohol solvents such
  • the conditions such as the reaction temperature, reaction time and amount of the reaction raw material in each of the above steps are not particularly limited, and the conditions under which the reaction can be sufficiently performed according to the desired yield ratio and the process effect desired by those skilled in the art can be selected and set appropriately.
  • the solvent used in the reaction is distilled and subjected to a post-treatment such as ordinary washing, drying and refining to obtain a high-purity compound.
  • the present invention provides the use of a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the prophylaxis or treatment of neurodegenerative diseases.
  • the present invention provides a method for treating a neurodegenerative disease, which comprises administering to a subject in need thereof an effective amount of a composition comprising the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the "effective amount” of the present invention refers to an amount that, when administered to an individual, represents an improvement, treatment, prevention, detection, diagnosis, or inhibitory effect of a degenerative neurological disease, It may be an animal including a human, and may be an animal-derived cell, tissue, organs and the like. The subject may be a patient requiring the effect.
  • " treatment " of the present invention broadly refers to ameliorating the symptoms of a degenerative neurodegenerative or neurodegenerative disease, which may include curing, substantially preventing, or ameliorating the condition, But is not limited to, alleviating, curing or preventing one or most symptoms of a neurological disorder.
  • the compound of the present invention When the compound of the present invention is applied to a neurodegenerative disease such as a real Alzheimer's disease, it has remarkable therapeutic effects such as A ⁇ plaque reduction, neuroinflammation, memory and anxiety improvement by controlling abnormal autophagy. Therefore, the compounds of the present invention can be very usefully used for the development of a preventive or therapeutic agent for degenerative neurological diseases through the control of autophagy.
  • FIG. 1 is a diagram showing an outline of an experiment carried out in order to examine the effect of a self-sustaining compound on Alzheimer's disease.
  • 5A-5D are results showing that injection of autophosphorylation enhancing compounds in APP / PS1 mice restored learning and cognitive function (WT: wild type, APP / PS1: Alzheimer's animal model).
  • FIG. 5B shows the time spent on the target platform on the 11th day of testing.
  • Figure 5c shows the number of times the target platform has entered the target area on the eleventh day of testing.
  • Figure 5d shows the results of the contextual and tone tasks during the fear conditioning test.
  • FIG. 6A is a graph plotting the area of the brain water in APP / PS1 mice injected with wild-type mouse (WT), PBS-injected APP / PS1 mouse, autophosphorylated compound and immunofluorescent staining of astrocytes (GFAP) Wreath is the result.
  • WT wild-type mouse
  • GFAP immunofluorescent staining of astrocytes
  • Figure 6b shows the results of immunofluorescent staining of microglial cells (Iba-1) in the brain water and hippocampus of APP / PS1 mice injected with wild-type mouse (WT), PBS-injected APP / PS1 mouse, The area is the result of quantifying wreaths.
  • Iba-1 microglial cells
  • FIG. 6c shows the effect of inflammatory markers (TNF-.alpha., IL-1.beta., IL-6) in the brain water of wild-type mice (WT), APP / PS1 mice injected with PBS and APP / PS1 mice injected with self- mRNA expression level of the cells.
  • WT wild-type mice
  • APP / PS1 mice injected with PBS
  • APP / PS1 mice injected with self- mRNA expression level of the cells.
  • Step 1 Preparation of methyl 2- (phenylsulfonyl) acetate
  • mice transgenic mouse lines overexpressing APPswe (hAPP695swe) and PS1 (presenilin-1M146V) based on C57BL / 6 mice (Charles River, UK) were used as animal models of degenerative neurological diseases (particularly Alzheimer's) / PS1 mouse (denoted by AD), GlaxoSmithKline]
  • the experimental material was administered to the animal model according to the experimental outline (schedule) shown in FIG. Specifically, 6.5-month-old mice were injected with PBS or an autophoresis-increasing compound at a dose of 50 mg / kg three times a week. Behavioral analysis was performed 2 months after the injection of the self-sustaining compound, and mouse brain tissue was used as a sample after behavioral analysis (i.e., mouse 9.5 weeks old) (see FIG. 1).
  • the primer pairs used in the real-time quantitative PCR are shown in Table 1.
  • MWM Morris water maze
  • fear conditioning experiments were performed to identify potential effects on learning and memory.
  • the mice were placed in a conditioning chamber and subjected to sound stimulation (10 kHz, 70 dB) and electrical stimulation (0.3 mA, 1 s).
  • sound stimulation 10 kHz, 70 dB
  • electrical stimulation 0.3 mA, 1 s
  • amyloid- ⁇ (A ⁇ ) profile and the level of tau protein deposition in Alzheimer's disease were examined.
  • cerebral cortex and hippocampal area of mouse were stained with thioflavin S (ThioS) according to a known method to confirm fibrillary amyloid- ⁇ deposition degree.
  • Immunofluorescent staining of A? 40, A? 42 and AT8 was also performed to confirm the degree of amyloid- ⁇ and tau protein deposition.
  • MWM Motor water maze
  • fear conditioning tests were conducted to confirm the potential effects of learning and cognitive abilities of self-sustaining compounds in Alzheimer's animals.
  • APP / PS1 mice exhibited severe impairment in spatial memory, cognition and memory formation, whereas APP / PS1 mice injected with autophagy boosting compounds showed significant improvement in this disorder 5A-5C). Also, it was confirmed that the self-phagocyte-increasing compound exhibited remarkable memory improvement effect even in the fear conditioning test (Fig. 5d).
  • the present inventors investigated the changes in astrocyte cells (using GFAP as a marker) and myocytes (using Iba-1 as a marker) in the brain Respectively.
  • lysosomal hydrolase and p62 an indicator of self-predominant turnover
  • WT mice, APP / PS1 mice WT mice, APP / PS1 mice
  • cathepsin D and p62 expression were reduced in APP / PS1 mice injected with autophagy boosting compounds.
  • the present invention relates to novel phenylsulfonyloxazole derivatives and their use, and specifically relates to a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, Prevention, treatment or amelioration.
  • the compound of the present invention When the compound of the present invention is applied to a neurodegenerative disease such as an actual Alzheimer's disease, the therapeutic effect such as A? Plaque reduction, neuroinflammation, memory and anxiety improvement is remarkable. As a result, the compounds of the present invention can be very usefully used for the development of a preventive or therapeutic agent for degenerative neurological diseases, and thus are highly industrially applicable.

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Abstract

La présente invention concerne un nouveau dérivé d'oxazole phénylsulfonyle et son utilisation et, en particulier, un composé représenté par la formule chimique 1 dans la présente description ou un sel pharmaceutiquement acceptable de celui-ci, et leur utilisation pour la prévention, le traitement ou le soulagement d'une maladie neurodégénérative.
PCT/KR2019/000373 2018-01-10 2019-01-10 Nouveau dérivé d'oxazole phénylsulfonyle et son utilisation Ceased WO2019139365A1 (fr)

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KR20190085443A (ko) 2019-07-18
US11345671B2 (en) 2022-05-31

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